An Atlas of Genetic Variation Linking Pathogen-Induced Cellular Traits to Human Disease

Pathogens have been a strong driving force for natural selection. Therefore, understanding how human genetic differences impact infection-related cellular traits can mechanistically link genetic variation to disease susceptibility. Here we report the Hi-HOST Phenome Project (H2P2): a catalog of cellular genome-wide association studies (GWAS) comprising 79 infection-related phenotypes in response to 8 pathogens in 528 lymphoblastoid cell lines. Seventeen loci surpass genome-wide significance for infection-associated phenotypes ranging from pathogen replication to cytokine production. We combined H2P2 with clinical association data from patients to identify a SNP near CXCL10 as a risk factor for inflammatory bowel disease. A SNP in the transcriptional repressor ZBTB20 demonstrated pleiotropy, likely through suppression of multiple target genes, and was associated with viral hepatitis. These data are available on a web portal to facilitate interpreting human genome variation through the lens of cell biology and should serve as a rich resource for the research community. [Display omitted] •Heritable variation in 79 cellular responses to infection with 8 pathogens was assessed•Phenotypes segregate in biologically meaningful clusters•17 significant genome-wide associations with infection phenotypes were identified•Integration with clinical GWAS revealed SNPs associated with IBD and hepatitis Approaches are needed for a deeper understanding of how human genetics impacts disease susceptibility. Wang et al. present a catalog of cellular genome-wide association studies comprising 79 phenotypes in response to 8 pathogens. Combining this with clinical association data and experimental validation revealed mechanisms and connections to disease.